Process for the preparation of optionally substituted 2,3-indolinediones

ABSTRACT

An improved process for the preparation of optionally substituted 2,3-indolinediones which are useful as intermediates in the preparation of compounds having pharmacological activity which comprises reacting a 3,1-benzoxazine with an alkali or alkaline earth metal cyanide or a tetra-(C 1-4 ) alkylammonium cyanide to obtain a 2-imino-3-indolinone, which is then subjected to hydrolysis.

This is a division of application Ser. No. 966,200, filed Dec. 4, 1978,now U.S. Pat. No. 4,212,804.

This invention relates to a new and more efficient process for thepreparation of optionally substituted 2,3-indolinediones which areuseful in the preparation of compounds having pharmacological activity.

More particularly, the process of the present invention involves thepreparation of 2,3-indolinediones of the formula I: ##STR1## wherein Ris hydrogen; C₁₋₄ alkyl; C₃₋₆ alkenyl; C₃₋₆ alkynyl; unsubstitutedphenyl; phenyl substituted by one or two substituents independentlyselected from C₁₋₄ alkyl; C₁₋₄ alkoxy, fluoro, chloro and bromo;unsubstituted benzyl; or benzyl substituted on the benzene ring by oneor two substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,fluoro, chloro and bromo;

X is fluoro; chloro; bromo; C₁₋₄ alkyl; C₁₋₄ alkoxy; or nitro; or twoadjacent X's together may also form methylenedioxy; and

n is 0 or an integer 1 or 2, the two X's being the same or differentwhen n is 2.

The 2,3-indolinediones of formula I are prepared by a two-step procedureinvolving in a first Step 1, the reaction of a 3,1-benzoxazine offormula II: ##STR2## wherein R, X and n are as defined above, with analkali or alkaline earth metal cyanide or a tetra-(C₁₋₄)alkylammoniumcyanide in a molar ratio of cyanide compound to a compound of formula IIof about at least 1:1, to decarboxylate and 3,1-benzoxazine and obtain a2-imino-3-indolinone of formula III: ##STR3## wherein R, X and n are asdefined above, said 2-imino-3-indolinone of formula III then beingsubjected in Step 2 to hydrolysis to obtain the 2,3-indolinedione offormula I.

The molar ratio of cyanide compound to compound of formula II in thepreparation of compounds of formula III is about at least 1:1. Althoughthe reaction may be conducted in the presence of a large excess of thecyanide compound, i.e., in a molar ratio of cyanide compound to compoundof formula II of 10:1, it is preferred that the reaction be conducted inabout an equimolar ratio or in the presence of a slight excess (e.g., upto 10%) of the cyanide compound.

The preparation of compounds of formula III by the decarboxylation ofcompounds of formula II employing an alkali or alkaline earth metalcyanide may be carried out at temperatures in the range of from 80° to140° C., preferably 90° to 120° C., and more preferably, at 100° C.Although the source of the cyanide ion may be any alkali or alkalineearth metal cyanide, the alkali metal cyanides are preferred, especiallysodium and potassium cyanide. The decarboxylation is carried out in thepresence of an organic solvent which is inert and adapted to dissolvingthe reactants and the product compound of formula III. Suitable solventsare known and available, and include by way of illustration, the liquid,di-lower alkyl amides of formic and acetic acids, preferablydimethylformamide. The resulting product of formula III may be isolatedfrom the reaction of Step 1 by working up by conventional procedures.

The preparation of compounds of formula III by the decarboxylation ofcompounds of formula II employing a tetra-(C₁₋₄) alkylammonium cyanidemay be carried out at temperatures in the range of from 10° to 80° C.,preferably 30° to 50° C., and more preferably, at 40° C. Although anytetra-(C₁₋₄) alkylammonium cyanide may be employed, a tetra-(C₁ or C₂)alkylammonium cyanide is preferred, more preferably, tetraethylammoniumcyanide. The decarboxylation is carried out in the presence of anorganic solvent which is inert and adapted to dissolving the reactantsand the product compound of formula III. Suitable solvents are known andavailable and include by by way of illustration, the chlorinatedhydrocarbons, preferably methylene chloride. The resulting product offormula III may be isolated from the reaction of Step 1 by working up byconventional techniques.

The preparation of compounds of formula I by Step 2 involving thehydrolysis of a compound of formula III is desirably effected underalkaline, neutral or acid conditions, preferably mild acidic conditions,suitably using hydrochloric or sulfuric acid, preferably hydrochloricacid. The hydrolysis may be carried out conveniently at a temperature offrom -40° to 100° C., preferably at a temperature of from 10° to 30° C.The resulting product of formula I may be isolated from the reactionmixture of Step 2 by working up by established procedures.

The 3,1-benzoxazines of formula II employed as starting materials inStep 1 are either known and obtained by methods described in theliterature, or where not known, may be obtained by methods analogous tothose described in the literature.

The 2-imino-3-indolinones of formula III, which are produced by thereaction of Step 1, are novel compounds and also form part of thisinvention.

The compounds of formula I are known and, as previously indicated, arevaluable intermediates in that they are useful in preparing compoundshaving pharmacological properties. The compound of formula I and aprocess for converting them into compounds having pharmacologicalactivity are disclosed in U.S. Pat. No. 4,020,179, U.S. Pat. No.3,509,149, British Pat. No. 975,357 and Sci. Pharm. 38(2), 98-106(1970).

Among the compounds for which the process of this invention is usefulare compounds of formula I and the novel intermediate compounds offormula III wherein:

(1) R is hydrogen, C₁₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, unsubstitutedphenyl or unsubstituted benzyl, and n is 0;

(2) R is C₁₋₄ alkyl, X is C₁₋₄ alkyl, fluoro, chloro or bromo, and n is1; and

(3) R is hydrogen, X is fluoro, chloro or bromo, and n is 1.

The following examples are for purposes of illustration only and are notintended to in any way limit the scope of the invention.

EXAMPLE 1 1-methyl-2,3-indolinedione ##STR4## Step 1: Preparation of2-imino-1-methyl-3-indolinone

To a suspension of 1.3 g. (0.021 moles) of pulverized potassium cyanidein 75 ml. of dimethylformamide (distilled over calcium hydride) at 100°C. is added dropwise, over a period of 15 minutes, a solution containing3.6 g (0.02 moles) of 1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione in 35ml. of dimethylformamide (distilled over calcium hydride), after whichtime the reaction mixture is stirred at 100° C. for an additional 5minutes. The resultant mixture is then poured into cold water andextracted into three 250 ml. portions of ether. After drying the organicphase over sodium sulfate, the excess solvent is removed and theresultant precipitate is filtered, washed with ether and dried in vacuoto yield 2-imino-1-methyl-3-indolinone, m.p.99°-120° C. (Yield: 49%).

Step 2: Preparation of 1-methyl-2,3-indolinedione

A suspension of 100 mg. of 2-imino-1-methyl-3-indolinone in 5 ml. of2N-hydrochloric acid is warmed slightly on a steam bath and allowed tostand at ambient temperature for one hour, after which time theresultant precipitate is filtered, washed with water and dried in vacuoto yield 1-methyl-2,3-indolinedione, m.p. 134°-136° C.

EXAMPLE 2

Following essentially the procedure of Example 1, and using in place of1-methyl-2H,-3,1-benzoxazine-2,4(1H)-dione in Step 1, an equivalentamount of:

(a) 6,7-dimethoxy-1-methyl-2H-3,1-benzoxazine-2,4-(1)-dione,

(b) 1-(2-propynyl)-2H-3,1-benzoxazine-2,4-(1H)-dione,

(c) 1-(2-propenyl)-2H-3,1-benzoxazine-2,4-(1H)-dione, or

(d) 1-benzyl-2H-3,1-benzoxazine-2,4-(1H)-dione, there is obtained

(a) 6,7-dimethoxy-2-imino-1-methyl-3-indolinone, m.p. 134°-138° C.(Yield: 14%),

(b) 2-imino-1-(2-propynyl)-3-indolinone, m.p. 121°-123° C. (Yield: 50%),

(c) 2-imino-1-(2-propenyl)-3-indolinone, an oil (Yield: 77%), and

(d) 1-benzyl-2-imino-3-indolinone, m.p. 81°-83° C. (Yield: 66%),respectively.

EXAMPLE 3

Following essentially the procedure of Example 1, and using in place of2-imino-1-methyl-3-indolinone in Step 2, an equivalent amount of each ofthe compounds obtained in Example 2, there is obtained

(a) 6,7-dimethoxy-1-methyl-2,3-indolinedione,

(b) 1-(2-propynyl)-2,3-indolinedione, m.p. 153°-155° C. (Yield: 85%),

(c) 1-(2-propenyl)-2,3-indolinedione, m.p. 82°-84° C. (Yield: 65%), and

(d) 1-benzyl-2,3-indolinedione, m.p. 127°-128° C., respectively.

EXAMPLE 4 1-methyl-2,3-indolinedione ##STR5## Step 1: Preparation of2-imino-1-methyl-3-indolinone

500 mg. of 1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione and 500 mg. oftetraethylammonium cyanide is added to 15 ml. of methylene chloride andthe reaction mixture is refluxed for 31/2 hours, after which time thereaction mixture is washed successively with water and a saturatedsodium chloride solution. After drying the organic phase over sodiumsulfate, the excess solvent is removed to yield crude, oily2-imino-1-methyl-3-indolinone, which can be purified to yield thedesired compound in crystalline form.

Step 2: Preparation of 1-methyl-2,3-indolinedione

Following essentially the procedure of Step 2 in Example 1, the2-imino-1-methyl-3-indoline prepared in Step 1 is hydrolyzed to yield1-methyl-2,3-indolinedione.

What is claimed is:
 1. A process for the preparation of a 2-imino-3-indolinone of the formula, ##STR6## wherein R is hydrogen; C₁₋₄ alkyl; C₃₋₆ alkenyl; C₃₋₆ alkynyl; unsubstituted phenyl; phenyl substituted by one or two substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro and bromo, unsubstituted benzyl; or benzyl substituted on the benzene ring by one or two substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro and bromo;X is fluoro; chloro; bromo; C₁₋₄ alkyl; C₁₋₄ alkoxy; or nitro; or two adjacent X's together may also form methylenedioxy; and n is 0 or an integer 1 or 2, the two X's being the same or different when n is 2,which comprises reacting a 3,1-benzoxazine of the formula, ##STR7## wherein R, X and n are as defined above, with an alkali or alkaline earth metal cyanide or a tetra-(C₁₋₄) alkylammonium cyanide in an equimolar ratio or in the presence of a slight excess of the cyanide compound, to decarboxylate said 3,1-benzoxazine and obtain said 2-imino-3-indolinone.
 2. The process according to claim 1 in which the 3,1-benzoxazine is reacted with an alkali metal cyanide at a temperature of from about 80° to 140° C.
 3. The process according to claim 2 wherein the 3,1-benzoxazine is reacted with an alkali metal cyanide at a temperature of from about 90° to 120° C.
 4. The process according to claim 2 wherein the alkali metal cyanide is potassium cyanide.
 5. The process according to claim 1 in which the 3,1-benzoxazine is reacted with a tetra(C₁₋₄) alkylammonium cyanide at a temperature of from about 10° to 80° C.
 6. The process according to claim 5 wherein the 3,1-benzoxazine is reacted with a tetra-(C₁₋₄) alkylammonium cyanide at a temperature of from about 30° to 50° C.
 7. The process according to claim 5 wherein the tetra-(C₁₋₄) alkylammonium cyanide is tetraethylammonium cyanide.
 8. The process according to claim 1 in which the 3,1-benzoxazine is reacted with potassium cyanide in an equimolar ratio or in the presence of a slight excess of potassium cyanide at a temperature of 100° C., to decarboxylate said 3,1-benzoxazine and obtain a 2-imino-3-indolinone.
 9. The process according to claim 1 in which the 3,1-benzoxazine is reacted with tetraethylammonium cyanide in an equimolar ratio in the presence of a slight excess of tetraethylammonium cyanide at a temperature of 40° C., to decarboxylate said 3,1-benzoxazine and obtain a 2-imino-3-indolinone.
 10. A compound of the formula, ##STR8## wherein R is hydrogen; C₁₋₄ alkyl; C₃₋₆ alkenyl; C₃₋₆ alkynyl; unsubstituted phenyl; phenyl substituted by one or two substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro and bromo; unsubstituted benzyl; or benzyl substituted on the benzene ring by one or two substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro and bromo;X is fluoro; chloro; bromo; C₁₋₄ alkyl; C₁₋₄ alkoxy; or nitro; or two adjacent X's together may also form methylenedioxy; and n is 0 or an integer 1 or 2, the two X's being the same or different when n is
 2. 